Multilaminate backing construction

ABSTRACT

A novel backing construction for a transdermal drug delivery system is disclosed. In particular, the invention relates to a system and method for labeling a transdermal drug delivery system, wherein the backing layer contains a writable medium capable of inkless printing.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/734,604 filed on Jun. 9, 2015, which is a continuation of U.S.application Ser. No. 11/842,048, filed Aug. 20, 2007, now issued as U.S.Pat. No. 9,078,833, which is a continuation of U.S. application Ser. No.10/646,539, filed Aug. 22, 2003, which claims the benefit of U.S.Provisional Patent Application No. 60/407,126, filed Aug. 30, 2002. Thisapplication hereby incorporates by reference the U.S. applications andprovisional application enumerated herein.

TECHNICAL FIELD

The present invention relates to a multilaminate backing constructionfor a transdermal drug delivery system. In particular, the inventionrelates to a system and method for labeling a transdermal drug deliverysystem, wherein the outermost layer of the multilaminate backingconstruction contains an embossable and writable material.

BACKGROUND OF THE INVENTION

The use of microporous materials, including films, in label applicationfor various packaging materials, containers, stationary, blood bags,recording paper, bandages and the like has been described in greatdetail. The following patents U.S. Pat. Nos. 6,255,552; 6,162,858;5,906,830; 5,871,829; 5,583,171; 5,507,525; 5,484,603; 5,314,421;4,751,087; 4,334,530 and 3,928,099 describe various ways of labelingpackaging materials, containers, stationary, blood bags and recordingpaper wherein sheet materials, e.g., microporous materials, containingadditives such as inorganic powder, printing inks, swellable agents,coloring agents, fillers etc. are used to create markings, e.g.,etching, scoring, printing, and writing, on the label. In general, theseprocesses require the use of high temperatures and/or the presence ofadditives within the microporous film in order to display the markingson the surface.

Labeling or printing information on transdermal systems has been achallenge. For example, use of printing inks, coloring agents, solventsand other additives necessary for printing may adversely interact withthe active agents within the transdermal system. To address theseconcerns, transdermal systems have been labeled using a process notrequiring the use of inks. The backing layer of the transdermal systemis labelled by a thermal embossing process. The polyolefin face of thebacking material is melted under pressure to reveal the label.

Notwithstanding some success, the existing technology for labelingtransdermal systems has not been entirely satisfactory. The additives inthe backing layer and/or the adjacent layers can interact adversely withthe active agents. Additionally the use of high temperatures to labelthe transdermal systems may degrade various components of thetransdermal systems or cause adhesive flow beyond the perimeter of thebacking. These challenges would in turn affect the potency and stabilityof the transdermal systems.

Further, the microporous films described previously are directlylaminated to a pressure sensitive adhesive to provide labels having goodadhesion. However, embossing microporous film after direct lamination toa pressure sensitive adhesive would be problematic. Embossing suchmicroporous films would result in a poorly resolved image due to theslow intrusion of the adhesive into the opaque film layer. The slowadhesive flow into the pores, accompanied by the crushing of the poresdue to embossing would render the film transparent. Further, theembossed image would be poorly resolved due to adhesive flow into thepores.

SUMMARY OF THE INVENTION

The present invention is directed to the aforementioned needs in theart, and provides a transdermal system having a multilaminate backingconstruction. In particular, the invention relates to a system andmethod for labeling a transdermal drug delivery system, wherein theoutermost layer of the multilaminate backing layer contains anembossable and writeable material.

In one aspect, the invention relates to a multilaminate backingconstruction comprising

(a) an outer layer comprising an embossable and writable material;

(b) a tie layer, the tie layer disposed on the skin proximal surface ofthe outer layer; and

(c) a base layer disposed on the skin proximal surface of the tie layer.

In another aspect, the multilaminate backing construction of theinvention comprises

(a) an outer layer comprising an embossable and writable material,wherein the outer layer is a microporous layer or a microfibrullarlayer;

(b) a tie layer comprising a secondary drug-containing reservoir, thetie layer disposed on the skin proximal surface of the outer layer; and

(c) a base layer disposed on the skin proximal surface of the tie layer.

In another aspect, the multilaminate backing construction of theinvention comprises

(a) an outer layer comprising an embossable and writable material,wherein the outer layer is a microporous layer or a microfibrullarlayer, wherein the outer layer is also a drug release rate controllingmeans;

(b) a tie layer comprising an antagonist-containing reservoir, whereinthe antagonist-containing reservoir is disposed on the skin proximalsurface of the outer layer; and

(c) a base layer disposed on the skin proximal surface of the tie layer.

In another aspect, the multilaminate backing construction of theinvention comprises

(a) an outer layer comprising an embossable and writable material,wherein the outer layer is a microporous layer or a microfibrullarlayer;

(b) a tie layer comprising a secondary drug-containing reservoir, thereservoir comprising a beneficial agent, the secondary drug-containingreservoir being disposed on the skin proximal surface of the outerlayer; and

(c) a base layer disposed on the skin proximal surface of the tie layer,wherein the base layer is a drug release rate controlling means.

In another aspect, the multilaminate backing construction of theinvention comprises

(a) an outer layer comprising an embossable and writable material,wherein the outer layer is a microporous layer or a microfibrullarlayer;

(b) a multilaminate tie layer, the tie layer disposed on the skinproximal surface of the outer layer, wherein the tie layer may contain asecondary drug-containing reservoir; and

(c) a base layer disposed on the skin proximal surface of the tie layer.

In additional aspects, the multilaminate backing construction of theinvention comprises a base layer impermeable to the drug within the drugreservoir or the tie layer; wherein the base layer comprises a materialwhich is insoluble in water, alcohol and organic solvents. The baselayer may optionally be a multilaminate layer. In certain embodiments,the base layer may be a drug release rate controlling means, e.g., adrug release rate controlling membrane. The base layer comprises apolymer such as polyolefin laminates (Dow Chemical, Midland, Mich.),acrylonitrile copolymer films (BAREX, BP Chemicals, Koln, Germany),polyethylnapthalene (PEN), polyethylene terephthalate (PET), PETmodified with adhesion improvement coatings such polyacrylates orpolyesters, polyimide, polyurethane, polyethylene, metallized films andglass coated films where these films can include ethylene copolymerssuch as ethylene-vinyl acetate copolymer (EVA), and combinationsthereof. In preferred embodiments, the base layer comprises polyester,such as PET, laminated to a polymer, such as polyurethane, polyethylene,and ethylene copolymers.

In preferred embodiments, the base layer is comprised of a polymericmaterial selected from the group consisting of a polyester-polyolefinmaterial such as Scotchpak 9735 (PET-PE laminate, 3M), Mediflex 1500(PET-pigmented EVA laminate, Mylan Technologies), Mediflex 1200 (PET-EVAlaminate, Mylan Technologies); Mediflex 1000 (a translucent polyolefinfilm, Mylan Technologies), Medifilm 500 series (EVA membrane material,Mylan Technologies); polyethylenes such as low density polyethylene(LDPE), medium density polyethylene (MDPE), high density polyethylene(HDPE), Kapton polyimide film, and other ethylene copolymer films suchas EMA, or EBA copolymer films.

In additional aspects, the multilaminate backing construction of theinvention comprises an outer layer comprising an embossable andwriteable material. The outer surface can be scribed with a pen, and canbe embossed by applying pressure with an embossing roll before or afterlamination of the multilaminate backing construction to a pressuresensitive adhesive. The outer layer comprises a breathable materialcomprising, porous, microporous, microfibrullar, spun-bonded, spunlaced, track etched, rayon (synthetic textile fibers produced by forcinga cellulose solution through fine spinnerets and solidifying theresulting filaments), wood-pulp, spun laced polyester, coated paperproducts, and the like, and a combination thereof. In preferredembodiments, outer layer comprises low density polyethylene (LDPE)materials, medium density polyethylene (MDPE) materials or high densitypolyethylene (HDPE) materials, and the like. In preferred embodiments,the outer layer is a single HDPE layer. In additional preferredembodiments, the outer layer comprises a microporous layer selected fromthe group consisting of Solupor microporous UHDPE P01 film (Solupor™manufactured by DSM Desotech, the Netherlands), microporouspolypropylene, e.g. Celgard microporous PP 3401 film (Celgard™ film,Celgard, Inc., Charlotte, N.C.), RoTrac Polyester Capillary PoreMembranes (OYPHEN GmbH, Germany), spun laced polyester, polypropylene orpolyethylene.

In additional aspects, the multilaminate backing construction of theinvention comprises a tie layer, wherein the tie layer may bemultilaminate. The tie layer is comprised of materials having a lowmelting point that flow easily at high temperatures to allow laminationto the outer layer. The tie layer may be formed from standard materialsas known in the art. For example, the tie layer is formed from ahydrophobic, a lipophilic and/or a non-polar polymeric material, suchas, ethyleneoctene copolymers such as ENGAGE 8407 (from Dupont-DowElastomers), ethylene-vinyl acetate copolymer (EVA), low densitypolyethylene (LDPE), medium density polyethylene (MDPE), non pressuresensitive formulation of styrenic block copolymer thermoplasticelastomers, and the like. In preferred embodiments, the tie layer isformed from ethyleneoctene copolymers, as described in greater detailbelow.

In additional aspects, the tie layer comprises a secondarydrug-containing reservoir. The secondary drug-containing reservoir maycontain a beneficial agent or an antagonist for the beneficial agent,wherein the antagonist is in a form that is not releasable through thebase layer. The skin distal surface of the drug reservoir is disposed onthe outer surface. The secondary drug-containing reservoir may be thesame size as the other layers of the backing construction or thesecondary drug-containing reservoir may be inset from the edge of thedie cut backing construction.

In certain embodiments, the secondary drug-containing reservoircomprises the drug dispersed within a polymer, wherein the drug issubstantially insoluble in the secondary drug-containing reservoirpolymer. In certain embodiments, the drug is dispersed in a matrixcomprising a material which substantially prevents release of the drug;or the drug is complexed with an ionic resin. In additional embodiments,the secondary drug-containing reservoir comprises the drug in amultiparticulate form, wherein each particle is individually coated witha material which substantially prevents release of the drug. Inadditional embodiments, the secondary drug-containing reservoircomprises beads coated with the drug, wherein the beads may be formedfrom glass or an inert or non-dissolvable polymer, and further whereinthe coated beads are optionally coated with or dispersed in materialwhich substantially prevents release of the drug. In preferredembodiments, the drug is an opioid antagonist selected from the groupconsisting of naltrexone, methylnaltrexone, naloxone, nalbuphine,nalorphine, nalorphine dinicotinate, nalmefene, nadide, levallorphan,cyclozocine and pharmaceutically acceptable salts thereof. In preferredembodiments, the antagonist is present as a salt, preferably as ahydrochloride salt of an antagonist base.

These and other embodiments of the present invention will readily occurto those of ordinary skill in the art in view of the disclosure herein.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 illustrates a cross-section through a schematic, perspective viewof one embodiment of multilaminate backing construction according tothis invention.

FIG. 2 illustrates a cross-section through a schematic, perspective viewof another embodiment of multilaminate backing construction according tothis invention.

DETAILED DESCRIPTION OF THE INVENTION

Overview:

The present invention is directed to a transdermal system having amultilaminate backing construction wherein the outermost layer of themultilaminate backing construction can be embossed and be written uponwith a pen or pencil. In particular, the outermost layer of themultilaminate backing construction of the present invention contains anembossable and writable material such as a microporous or microfibrillarfilm, which is laminated via a tie layer to a base layer.

DEFINITIONS

In describing and claiming the present invention, the followingterminology will be used in accordance with the definitions set outbelow.

The singular forms “a,” “an” and “the” include plural referents unlessthe context clearly dictates otherwise. Thus, for example, reference to“a polymer” includes a single polymer as well as a mixture of two ormore different polymers, reference to “a permeation enhancer” includes asingle permeation enhancer as well as two or more different permeationenhancer in combination, and the like.

As used herein, the term “drug release controlling means” refers to ameans to control/regulate the release of a drug from the secondarydrug-containing reservoir.

As used herein, the terms “drug” and “active agent” are usedinterchangeably and are to be construed in the broadest sense to meanany material which is intended to produce some biological, beneficial,therapeutic, or other intended effect, such as permeation enhancement,an antagonist, on the organism to which it is applied. For example, thedrug may be a beneficial agent or an antagonist of the beneficial agent.

Modes of Carrying Out the Invention

The present invention provides a multilaminate backing construction fora transdermal drug delivery system, the outermost layer of themultilaminate backing construction having an embossable and writablematerial.

Referring now to FIG. 1, a preferred embodiment of the multilaminatebacking construction 1 according to this invention comprises an outerlayer 2, a tie layer 3 wherein the skin distal surface of the tie layeris disposed on the outer layer 2, and a base layer 4 wherein the tielayer 3 is disposed on the skin distal surface of the base layer 4. Incertain embodiments of the backing construction 1 of the invention, thetie layer 3 is a secondary drug-containing reservoir disposed on theskin proximal surface of the outer layer 2, and the base layer 4 isdisposed on the skin proximal surface of the secondary drug-containingreservoir. The secondary drug-containing reservoir may contain abeneficial agent or an antagonist for a beneficial agent. In certainembodiments of the backing construction 1 of the invention, wherein thesecondary drug-containing reservoir contains a beneficial agent, thebase layer 4 is a drug rate controlling means disposed on the skinproximal surface of the secondary drug-containing reservoir. Inalternative embodiments of the backing construction 1 of the invention,the secondary drug-containing reservoir contains an antagonist of abeneficial agent, and preferably, the outer layer also functions as anantagonist release rate controlling means.

Referring now to FIG. 2 a preferred embodiment of the multilaminatebacking construction 11 according to this invention comprises an outerlayer 12, a multilaminate tie layer 13 and a base layer 14. The tielayer comprises a first layer 16 disposed on the skin proximal surfaceof the outer layer 12; a second layer 17 disposed on the skin proximalsurface of the first layer 16; a third layer 18 disposed on the skinproximal surface of the second layer 17; and a secondary drug-containingreservoir 15. The base layer 14 is configured to provide a centralvolume which contains the secondary drug-containing reservoir 15 in theform of a gel having dissolved or suspended drug therein. In preferredembodiments, the first layer 16 is an EVA or LDPE layer, the secondlayer 17 is a PET layer, the third layer 18 is an EVA, LOPE or apolyurethane layer; and the base layer 14 is a drug release ratecontrolling means.

The outer layer 2, 12, of the multilaminate backing construction of theinvention comprises an embossable and writeable material. The outersurface can be scribed with a pen, and can be embossed by applyingpressure with an embossing roll before or after lamination of themultilaminate backing construction to a pressure sensitive adhesive. Theouter layer comprises a breathable material comprising, porous,microporous, microfibrullar, spun-bonded, spun laced, track etched,rayon (synthetic textile fibers produced by forcing a cellulose solutionthrough fine spinnerets and solidifying the resulting filaments),wood-pulp, spun laced polyester, coated paper products, and the like,and a combination thereof. In preferred embodiments, outer layercomprises low density polyethylene (LDPE) materials, medium densitypolyethylene (MDPE) materials or high density polyethylene (HDPE)materials, and the like. In preferred embodiments, the releasecontrolling means is a single LDPE layer. In additional preferredembodiments, the outer layer comprises a microporous layer selected fromthe group consisting of Solupor microporous UHDPE P01 film (Solupor™manufactured by DSM Desotech, the Netherlands), microporouspolypropylene, e.g. Celgard microporous PP 3401 film (Celgard™ filmmanufactured by Celgard, Inc., Charlotte, N.C.), RoTrac PolyesterCapillary Pore Membranes (OYPHEN GmbH, Switzerland), spun lacedpolyester, polypropylene or polyethylene. The outer layer is free of anyadditives and is not directly laminated to a pressure sensitiveadhesive. Alternatively, the outer layer can be coated with low levelsof surfactants, for example, pluronic polyethylene oxide-polypropyleneoxide block copolymers and the like, to provide further control over therate of drug release from the underlying tie layer.

The outer layer 2, 12, has a thickness of about 0.012 mm (0.5 mil) toabout 0.125 mm (5 mil); preferably 0.025 mm (1 mil) to about 0.1 mm (4mil); more preferably 0.0375 mm (1.5 mil) to about 0.0875 mm (3.5 mil);and even more preferably 0.05 mm (2 mil) to about 0.0625 mm (2.5 mil).

The multilaminate backing construction according to the inventioncomprises a tie layer 3, 13, wherein the tie layer may be multilaminate.The tie layer is comprised of materials having a low melting point thatflow easily at high temperatures to allow lamination to the outer layer2, 12, such materials excluding pressure sensitive adhesives and HDPE.HDPE has a very high melting point and its use in the outer layer wouldrender the embossable film prematurely clear due to high laminatingtemperatures and coincidental melting of the outer layer. Incorporationof pressure sensitive materials in the outer layer would result in flowof the adhesive into the pores, which would result in the embossablefilm prematurely turning clear. In certain embodiments, the tie layercomprises a secondary drug-containing reservoir. The secondarydrug-containing reservoir may contain a beneficial agent or anantagonist for the beneficial agent. In certain embodiments, when thesecondary drug-containing reservoir contains an antagonist, the outerlayer also functions as a drug release rate controlling means. Incertain embodiments, when the second drug-containing reservoir containsa beneficial agent, the base layer 4 is a drug release rate controllingmeans is disposed on the skin proximal surface of the secondarydrug-containing reservoir. The secondary drug-containing reservoir maybe THE same size as the other layers of the backing construction or thesecondary drug-containing reservoir may be inset from the edge of thedie cut backing construction. The tie layer may be formed from standardmaterials as known in the art. In particular, the tie layer 3, 13, isformed from low melting materials that flow easily at high temperaturesand exclude pressure sensitive adhesives and HDPE. For example, the tielayer is formed from a hydrophobic, a lipophilic and/or a non-polarpolymeric material, such as, ethyleneoctene copolymers such as ENGAGE8407 (from Dupont-Dow Elastomers), ethylene-vinyl acetate copolymer(EVA), low density polyethylene (LDPE), medium density polyethylene(MDPE), styrenic block copolymer thermoplastic elastomers, PET,polyurethanes, and the like. In preferred embodiments, the tie layer isformed from ethyleneoctene copolymers, as described in greater detailbelow.

In certain embodiments wherein the tie layer contains a secondarydrug-containing reservoir, particularly an antagonist-containingreservoir, the antagonist is dispersed in a matrix comprising apolymeric material which substantially prevents release of theantagonist, preferably a thermoformable material; or the antagonist iscomplexed with an ionic resin. In additional embodiments, theantagonist-containing reservoir comprises the antagonist in amultiparticulate form, wherein each particle is individually coated witha polymeric material which substantially prevents release of theantagonist, wherein the polymeric material is preferably athermoformable material. In additional embodiments, theantagonist-containing reservoir comprises beads coated with theantagonist, wherein the beads may be formed from glass or an inert ornon-dissolvable polymer, and further wherein the coated beads areoptionally coated with or dispersed in a polymeric material whichsubstantially prevents release of the antagonist, wherein the polymericmaterial is preferably a thermoformable material. Examples of antagonistinclude, but are not limited to, naltrexone, methylnaltrexone, naloxone,nalbuphine, nalorphine, nalorphine dinicotinate, nalmefene, nadide,levallorphan, cyclozocine and the like, and pharmaceutically acceptablesalts thereof. Preferably, the antagonist is present as a salt.

As discussed above, the antagonist-containing reservoir comprises theantagonist dispersed within a polymer. Preferably, the antagonist isdispersed in a matrix comprising a thermoformable material whichsubstantially prevents release of the antagonist. Alternatively, theantagonist is present in a multiparticulate form, wherein each particleis individually coated with a polymeric material which substantiallyprevents release of the antagonist. Preferably, the polymeric materialwhich substantially prevents release of the antagonist ishydrophobic—i.e., substantially prevents release of the antagonistduring normal use, minimizes the amount of antagonist duringincidental/casual exposure to solvents (moisture e.g., sweat, during ashower), and upon ingestion or immersion in a solvent, releases theantagonist in abuse limiting amounts. Preferably, the polymeric materialhas a low melting point to allow processing of the antagonist in solidphase and to prevent degradation of the antagonist. Examples of apolymeric material which substantially prevents release of theantagonist include, but are not limited to, polyethylene, polyoctene,polyvinyl acetate, polymethyl acrylate, polymethyl acrylate, polyethylacrylate, polystyrene polymers and copolymers and mixtures thereof;polystyrene copolymers such as styrenic block copolymers (SIS, SBS,SEBS), ethylene copolymers such as polyethyleneoctene copolymers,ethylene-vinyl acetate copolymer (EVA), ethylenemethyl acrylatecopolymers (EMA), ethylene-acrylic acid copolymer,ethylene-ethylacrylate copolymer, and the like, and combinationsthereof.

In additional embodiments, the antagonist is complexed with an ionicresin. Examples of ionic resins include, but are not limited tosulfonated polystyrene resins, and the like. Preferably the resincontains a sulfonic acid functionality which when neutralized with theantagonist base forms the sulfonate salt of the antagonist.

In additional embodiments, the antagonist-containing reservoir comprisesbeads coated with the antagonist, wherein the spheres or beads may beformed from glass, metals or an inert or non-dissolvable polymer, andfurther wherein the coated beads are optionally coated with or dispersedin a polymeric material which substantially prevents release of theantagonist, as described above. The beads may be in any shape, size orform, but are preferably small sized, preferably less than 10 microns.Examples of an inert or non-dissolvable polymer include, but are notlimited to polymethylmethacrylate, polycarbonate and polystyrene.

In certain embodiments wherein the tie layer contains a secondarydrug-containing reservoir, the secondary drug-containing reservoir isdisposed on the skin proximal surface of the outer layer 2 and the skindistal surface of the base layer 4. The secondary drug-containingreservoir may be formed from standard materials as known in the art. Forexample, the secondary drug-containing reservoir is formed from ahydrophobic and/or lipophilic polymeric material, such as, hydrophobicpolyurethane, ethylene-vinyl acetate copolymer (EVA) and the like.

In preferred embodiments, when the drug is a beneficial agent, thesecondary drug-containing reservoir comprises about 5 to about 35 wt %of the drug; more preferably about 10 to about 35 wt % of the drug; andeven more preferably about 15 to about 30 wt % of the drug. Examples ofbeneficial agent include, but are no limited to, fentanyl, sufentanil,risperidone, gallantamine, norelgestromin, testosterone, estradiol,nicotine, methylphenidate, fenoldopam, and the like. Preferably, thematerial forming the secondary drug-containing reservoir has asolubility for the drug of about 5 wt % to about 40 wt % of the totalpolymer composition; more preferably about 10 wt % to about 35 wt %; andeven more preferably about 15 wt % to about 30 wt % of the total polymercomposition.

In additional preferred embodiments, the drug is an antagonist,preferably the antagonist is in the salt form and the preferredantagonists are naltrexone, methylnaltrexone, naloxone, nalbuphine,nalorphine, nalorphine dinicotinate, nalmefene, nadide, levallorphan andcyclozocine. When the drug is an antagonist of a beneficial agent, thesecondary drug-containing reservoir comprises about 20 to about 70 wt %of the drug; more preferably about 40 to about 65 wt % of the drug; andeven more preferably about 50 to about 60 wt % of the drug. Preferably,the material forming the secondary drug-containing reservoir 5 has asolubility for the drug of about 0 wt % to about 1 wt % of the totalpolymer composition; more preferably about 0 wt % to about 0.8 wt %; andeven more preferably about 0 wt % to about 0.5 wt % of the total polymercomposition.

The tie layer 3, 13, including the secondary drug-containing reservoir,has a thickness of about 0.0125 mm (0.5 mil) to about 0.1 mm (4 mil),preferably about 0.015 mm (0.6 mil) to about 0.0875 mm (3.5 mil); morepreferably 0.025 mm (1 mil) to about 0.08 mm (3.3 mil); and even morepreferably about 0.02 mm (1.6 mil) to about 0.075 (3 mil).

In additional embodiments, the secondary drug-containing reservoir mayoptionally contain additional components such as, permeation enhancers,stabilizers, diluents, antioxidants, excipients, gelling agents,anti-irritants, vasoconstrictors and other materials as are generallyknown to the transdermal art.

Examples of permeation enhancers include, but are not limited to, fattyacid esters of glycerin, such as capric, caprylic, dodecyl, oleic acids;fatty acid esters of isosorbide, sucrose, polyethylene glycol; caproyllactylic acid; laureth-2; laureth-2 acetate; laureth-2 benzoate;laureth-3 carboxylic acid; laureth-4; laureth-5 carboxylic acid;oleth-2; glyceryl pyroglutamate oleate; glyceryl oleate; N-lauroylsarcosine; N-myristoyl sarcosine; N-octyl-2-pyrrolidone;lauraminopropionic acid; polypropylene glycol-4-laureth-2; polypropyleneglycol-4-laureth-5dimethyl lauramide; lauramide diethanolamine (DEA).Preferred enhancers include, but are not limited to, laurylpyroglutamate (LP), glyceryl monolaurate (GML), glyceryl monocaprylate,glyceryl monocaprate, glyceryl monooleate (GMO), and sorbitanmonolaurate. Additional examples of suitable permeation enhancers aredescribed, for example, in U.S. Pat. Nos. 5,785,991; 5,843,468;5,882,676; and 6,004,578.

The multilaminate backing construction according to this inventioncomprises a base layer 4, 14, wherein the tie layer 3, 13, is disposedon the skin distal surface of the base layer 4, 14. The base layer 4,14, may be multilaminate. The base layer 4 comprises a polymer such aspolyolefin laminates (Dow Chemical, Midlane, Mich.), acrylonitrilecopolymer films (BAREX, BP Chemicals, Koln, Germany),polyethylnapthalene (PEN), polyethylene terephthalate (PET), polyimide,polyurethane, polyethylene, metallized films and glass coated filmswhere these films can include ethylene copolymers such as ethylene-vinylacetate copolymer (EVA), and combinations thereof. In preferredembodiments, the base layer comprises a polyester such as PET laminatedto a polymer such as polyurethane, polyethylene, and ethylenecopolymers. In certain embodiments, the base layer may be a drug ratecontrolling means, as described in greater detail hereinafter. Incertain embodiments wherein the secondary drug-containing reservoircontains an antagonist, the base layer 4 is impermeable to theantagonist within the secondary drug-containing reservoir; the baselayer comprising a material which is insoluble in water, alcohol andorganic solvents.

In preferred embodiments, the base layer is comprised of a polymericmaterial selected from the group consisting of a polyester-polyolefinmaterial such as Scotchpak 9735 (PET-PE laminate, 3M), Mediflex 1500(PET-pigmented EVA laminate, Mylan Technologies, Saint Albans, Vt.),Mediflex 1200 (PET-EVA laminate, Mylan Technologies, Saint Albans, Vt.);Mediflex 1000 (a translucent polyolefin film, Mylan Technologies, SaintAlbans, Vt.), Medifilm 500 series (EVA membrane material, MylanTechnologies, Saint Albans, Vt.); polyethylenes such as low densitypolyethylene (LDPE), medium density polyethylene (MDPE), high densitypolyethylene (HDPE), ethylene methyl acrylate copolymer (EMA), ethyleneethyl acrylate copolymer (EEA), or ethylene butyl acrylate copolymer(EBA) copolymers. The base layer has a thickness of about 0.01 mm (0.4mil) to about 0.125 mm (5 mil); preferably 0.025 mm (1 mil) to about 0.1mm (4 mil); more preferably 0.0625 mm (1.5 mil) to about 0.0875 mm (3.5mil); and even more preferably 0.025 mm (1 mil) to about 0.05 mm (2mil).

The multilaminate backing construction comprises a drug release ratecontrolling means, preferably within the outer layer or within the baselayer. In certain embodiments, when the secondary drug-containingreservoir is an antagonist-containing reservoir, the outer layer 2, 12,also functions as a drug release rate controlling means disposed on theskin distal surface of the secondary drug-containing reservoir. Inalternative embodiments, when the secondary drug-containing reservoircontains a beneficial agent, the base layer 4, 14, is a drug releaserate controlling means disposed on the skin proximal surface of thesecondary drug-containing reservoir. In preferred embodiments, the tielayer comprises an antagonist-containing reservoir, and the outer layeris a drug release controlling means.

The rate controlling means is made of a polymeric material such asethylene-vinyl acetate (EVA), polyvinyl chloride (PVC), ethylene-ethylacrylate copolymer, ethylene butylacrylate copolymer, polyisobutylene(PIB), polyethylene (PE) such as low density polyethylene (LDPE), mediumdensity polyethylene (MDPE), high density polyethylene (HDPE), and thelike, and a combination thereof; the polymeric materials may beplasticized. In preferred embodiments, the base layer is a drug releaserate controlling means and is adhered to the skin with an acrylic,silicone, polyisobutylene (PIB) or other pressure sensitive adhesivematerial. The rate controlling means has a thickness of about 0.012 mm(0.5 mil) to about 0.125 mm (5 mil); preferably 0.025 mm (0.6 mil) toabout 0.1 mm (4 mil); more preferably 0.0625 mm (0.8 mil) to about0.0875 mm (3.5 mil).

The multilaminate backing construction can be processed with lessstretching under web tension because of the less extensible outer layer,preferably the Solupor layer, which also provides a surface forembossing and writing.

The transdermal devices are manufactured according to known methodology.In general, the transdermal device according to this invention comprisesa backing construction 1, 11, a primary drug-containing reservoirdisposed on the backing construction, wherein at least the skincontacting surface of the primary drug-containing reservoir is adhesive,and a peelable protective layer. The multilaminate backing constructionis laminated via a pressure sensitive adhesive to a primarydrug-containing reservoir. The primary drug-containing reservoir istypically formed from a pharmaceutically acceptable pressure sensitiveadhesive but, in some cases, can be formed from a non-adhesive material.If the primary drug-containing reservoir is formed from a material thatdoes not have adequate adhesive properties, the primary drug-containingreservoir may be formulated with a thin adhesive coating. The primarydrug-containing reservoir intermediate is optionally laminated to a drugrelease-rate controlling membrane disposed between the primarydrug-containing drug reservoir and the peelable protective layer. Insubsequent operations, individual transdermal devices are die-cut,separated and unit-packaged using suitable pouchstock. Transdermaldevices are cartoned using conventional equipment. The resultingtransdermal delivery system provides a rate-controlled drug deliverydevice having embossing and writing capabilities.

Transdermal drug delivery systems having the multilaminate backingconstruction containing an antagonist-containing reservoir within thetie layer, when used in combination with opioid-delivering transdermalformulations, provide a deterrence to drug abusers attempting to misusethe systems, while at the same time, enable embossed labeling orscribing with a pen.

The multilaminate backing construction is embossed by application ofpressure without the application of high temperatures, and withoutmelting the outer layer. Simply applying pressure without increasing thetemperature is sufficient to provide a very striking visual graphic. Themethod of labeling a transdermal system using the multilaminate backingconstruction of the invention eliminates the need for solvent-based inkswhen printing transdermal systems by a heat-free embossing technique.Additionally, the method of the invention eliminates adversedrug-additive interactions, improving stability, thermal sensitivity,therapeutic effects, shelf-life and ease of manufacture of a transdermaldrug delivery system.

Additionally, the multilaminate backing construction of the invention iswritable, allowing physicians, nurses, or users to write directly on thebacking with a pen without the ink smearing. This feature is importantin many clinical settings because physicians and nurses need to indicateon multiple-day transdermal systems when replacement is required. If notreplaced at the appropriate time, sub-therapeutic quantities of drug maybe delivered as the drug content in the system depletes.

Further, when the multilaminate backing construction is laminated to aprimary drug-containing adhesive matrix, the drug cannot penetratethrough the multilaminate backing construction into the heat seal layerof the pouch material due to the microporous/microfibrous nature of theouter layer.

In additional embodiments, the multilaminate backing construction islaminated to a pressure sensitive adhesive, enabling bonding to anymedical device such as a blood bag, IV bag, or form-fill-sealtransdermal patch, e.g. Duragesic® transdermal fentanyl delivery system.

A wide variety of materials which can be used for fabricating thevarious layers of the multilaminate backing construction according tothis invention have been described above. This invention thereforecontemplates the use of materials other than those specificallydisclosed herein, including those which may hereafter become known tothe art to be capable of performing the necessary functions.

Methods of Manufacture

The multilaminate backing construction of the invention are manufacturedas follows. The drug-containing reservoirs are manufactured according toknown methodology, as described in greater detail below.

Drug-Containing Reservoir

The secondary drug-containing reservoir can be formed by dry blending adrug, with a polymeric material, preferable a thermoformable material,at high shear and temperature using equipment such as sigma blade mixersor extruders, either batch-wise or continuously. The extrudate iscalendered to the desired thickness between release liners, followed bylamination at elevated temperature to a barrier film and/or an analgesicrate controlling means. Parameters such as drug loading, drug-containingreservoir thickness, membrane selection for the rate controlling means,and surfactant modification of the rate controlling means can be variedto achieve the targeted release rate of drug, as illustrated in theExamples hereinafter. In preferred embodiments, surfactants are coatedonto membrane materials forming the rate controlling means usingtechniques such as dip-coating, gravure coating, and the like.

In alternative embodiments, the secondary drug-containing reservoirs aremanufactured according to known methodology as follows. A solution ofthe polymeric reservoir material, as described above, is added to adouble planetary mixer, followed by addition of desired amounts of thedrug, and optionally, a permeation enhancer. Preferably, the polymericsecondary drug-containing reservoir material is solubilized in anorganic solvent, e.g., ethanol, ethyl acetate, hexane, and the like. Themixer is then closed and activated for a period of time to achieveacceptable uniformity of the ingredients. The mixer is attached by meansof connectors to a suitable casting die located at one end of acasting/film drying line. The mixer is pressurized using nitrogen tofeed solution to the casting die. Solution is cast as a wet film onto amoving siliconized polyester web. The web is drawn through the lines anda series of ovens are used to evaporate the casting solvent toacceptable residual limits. The dried secondary drug-containingreservoir film is then laminated to a selected base layer and thelaminate is wound onto the take-up rolls. In another process, thesecondary drug-containing reservoir can be formed using dry-blending andthermal film-forming using equipment known in the art. Preferably, thematerials are dry blended and extruded using a slot die followed bycalendering to an appropriate thickness. Parameters such as drugloading, secondary drug-containing reservoir thickness, drug selections,material selections and manufacturing process can be varied forpreparing drug-containing reservoirs of the current invention, asillustrated in the Examples hereinafter.

The primary drug-containing reservoir is manufactured as described aboveusing known materials and according to known procedures.

Multilaminate Backing Construction

In general, the multilaminate backing construction is manufactured asfollows. For example, as illustrated in FIG. 1, the tie layer islaminated to the base layer, followed by lamination of the outer layeron the surface of the tie layer distal to the base layer at elevatedtemperature and pressure. Alternatively, both laminations could beconducted in a single operation by extruding the tie layer at therequired width and thickness directly between the outer layer and thebase layer prior to lamination. In general, the lamination is performedat a temperature ranging from about 70° C. to about 120° C., and apressure ranging from 50 psi to about 120 psi, at the rate ranging fromabout 2 fpm to about 20 fpm.

In an alternative embodiment, wherein the tie layer comprises asecondary drug-containing reservoir, the multilaminate backingconstruction, is manufactured by laminating sequentially orsimultaneously the secondary drug-containing reservoir layer to the baselayer and to the outer layer under lamination conditions as describedabove. The secondary drug-containing reservoir is manufactured asdescribed earlier.

In another embodiment of the multilaminate backing construction, asillustrated in FIG. 2, the tie layer is a multilaminate layer containingan outermost first layer 16 (EVA/LDPE layer) on the skin proximalsurface of the outer layer, laminated to a second layer 17 (PET layer)disposed on the skin proximal surface of the first layer 16, thebi-layer is further laminated to a third layer 18 (EVA/LDPE/polyurethanelayer) disposed on the skin proximal surface of the second layer 17, anda form fill type of a secondary drug-containing reservoir 15. The baselayer 14, e.g. a drug release rate controlling means, is configured toprovide a central volume which contains the secondary drug-containingreservoir 15 in the form of a gel having dissolved or suspended drugtherein.

EXPERIMENTAL

Below are examples of specific embodiments for carrying out the presentinvention. The examples are offered for illustrative purposes only, andare not intended to limit the scope of the present invention in any way.

Efforts have been made to ensure accuracy with respect to numbers used(e.g., amounts, temperatures, etc.), but some experimental error anddeviation should, of course, be allowed for.

Specific examples of various multilaminate backing construction of theinvention will be described in the examples set for hereinafter. In thefollowing examples all percentages are by weight unless noted otherwise.

Example 1

A polyester-polyolefin transdermal backing material such as Scotchpak9735 (PET-PE laminate, 3M, Cottage Grove, Minn.), Mediflex 1500(PET-pigmented EVA laminate, Mylan Technologies, Saint Albans, Vt.), orMediflex 1200 (PET-EVA laminate, Mylan Technologies) are laminated toSolupor microfibrous UHMW-HDPE P01 film (DSM Solutech, Heerlen, theNetherlands) at elevated temperature and pressure. The temperaturerequired for the lamination is above the melting point of the polyolefinlayer of the backing, usually above 100° C. The resulting multilaminateis used as a transdermal backing, the Solupor surface of which can bescribed with a pen, and which can be embossed by applying pressure withan embossing roll before or after lamination to a pressure sensitiveadhesive.

Example 2

Mediflex 1200, a polyester-EVA laminate, is bonded to a Solupormicrofibrous UHMW-HDPE film via a tie layer. The tie layer contains anENGAGE 8407 ethylene-octene copolymer (Dupont-Dow Elastomers, DSMSolutech's) containing a naltrexone hydrochloride dispersion. Adequatebonding is achieved by performing a hot lamination step at 90 psi, 5fpm, and 100° C. The resulting multilayered construction is laminated toa fentanyl-containing adhesive reservoir. The resulting construction isembossed for identification, can be written upon with a ballpoint pen,and contains the antagonist, naltrexone hydrochloride, to preventfentanyl abuse.

Example 3

A multilaminate backing construction using Celgard microporous PP 3401film (Celgard Microporous Membrane) is prepared, as described in Example1 above.

Example 4

A multilaminate backing construction using Rotrac Capillary PoreMembrane (Oxyphen, Zug, Switzerland) is prepared, as described inExample 1 above.

Example 5

A multilaminate backing construction using Celgard microporous PP 3401film is prepared, as described in Example 2 above.

Example 6

A multilaminate backing construction using Rotrac Capillary PoreMembrane (Oxyphen, Zug, Switzerland)microporous polyester is prepared,as described in Example 2 above.

Example 7

A translucent polyolefin film, Mediflex 1000 (Mylan Technologies, SaintAlbans, Vt.), is laminated to the Solupor microfibrous film P01 via alow melting Engage 8407 ethylene-octene copolymer. The conditionsrequired for the lamination are 80° C., 90 psi, and 3 fpm. The resultingtransdermal backing material can be processed with less stretching underweb tension because of the less extensible Solupor layer, which alsoprovides a surface for embossing and writing. Further, when this backingmaterial is laminated to a primary drug-containing adhesive matrix, drugcannot penetrate through the multi-layered backing into the heat seallayer of the pouch material because of the microfibrous nature of theSolupor layer.

Example 8

The procedure outlined in Example 7 is followed except an EVA film issubstituted for the LDPE film. The resulting construction provides thebenefits outlined in example 7 with the added benefit of providing anadditional drug reservoir in the EVA backing layer. Drug incorporationinto the EVA film is achieved during its extrusion or through the slowdiffusion of drug into the EVA after lamination to an activedrug-pressure sensitive adhesive reservoir.

Example 9

A LDPE or EVA membrane material such as the Medifilm 500 series fromMylan Technologies, is laminated to a polyolefin drug reservoirconsisting of an EVA-40 drug dispersion, which is, in turn, laminated tothe Solupor P01 film at 70° C., 50 psi, and 3 fpm on hot laminationequipment. The resulting multi-layered construction, after lamination toa pressure sensitive adhesive, provides rate-controlled drug delivery,embossing, and writing capabilities.

Example 10

Any of the multilayered constructions described in Examples 1-9 arelaminated to a pressure sensitive adhesive, enabling bonding to anymedical device such as a blood bag, IV bag, or form-fill-sealtransdermal patch such as Duragesic transdermal fentanyl deliverysystem.

The above-described exemplary embodiments are intended to beillustrative in all respects, rather than restrictive, of the presentinvention. Thus the present invention is capable of many variations indetailed implementation that can be derived from the descriptioncontained herein by a person skilled in the art. All such variations andmodifications are considered to be within the scope and spirit of thepresent invention.

The invention claimed is:
 1. A method of making a transdermal drugdelivery device, the method comprising: forming a device comprising aprimary drug-containing reservoir and multilaminate backingconstruction, wherein the primary drug-containing reservoir comprises aprimary drug selected from the group consisting of a therapeutic agentand an antagonist, and wherein the multilaminate backing constructioncomprises (a) an outer layer, (b) a tie layer comprising a secondarydrug-containing reservoir comprising a secondary drug selected from thegroup consisting of an antagonist and a therapeutic agent, wherein thesecondary drug is different from the primary drug, and (c) a base layer.2. The method of claim 1, wherein the tie layer is a multilaminate tielayer.
 3. The method of claim 2, wherein the multilaminate tie layercomprises: (i) a first layer disposed on the skin proximal surface ofthe outer layer; (ii) a second layer disposed on the skin proximalsurface of the first layer; (iii) a third layer disposed on the skinproximal surface of the second layer; and (iv) the secondarydrug-containing reservoir.
 4. The method of claim 3, wherein the firstlayer is ethylene-vinyl acetate copolymer (EVA) or low densitypolyethylene (LDPE) layer; the second layer is a polyethyleneterephthalate (PET) layer; and the third layer is an ethylene-vinylacetate copolymer (EVA), a low density polyethylene (LDPE), or apolyurethane layer.
 5. The method of claim 1, wherein the outer layercomprises a material selected from the group consisting of low densitypolyethylene (LDPE), medium density polyethylene (MDPE), high densitypolyethylene (HDPE), ultra high density polyethylene (UHDPE),polypropylene, and polyester.
 6. The method of claim 1, wherein the baselayer comprises a material selected from the group consisting ofpolyester-polyolefin laminate, low density polyethylene (LDPE), mediumdensity polyethylene (MDPE), high density polyethylene (HDPE), ethylenemethyl acrylate copolymer (EMA), ethylene ethyl acrylate copolymer(EEA), and ethylene butyl acrylate copolymer (EBA) copolymers.
 7. Themethod of claim 1, wherein the secondary drug-containing reservoirfurther comprises a polymeric matrix.
 8. The method of claim 7, whereinthe secondary drug is an antagonist, and wherein the antagonist isdispersed in the polymeric matrix.
 9. The method of claim 1, wherein thesecondary drug-containing reservoir further comprises a thermoformablepolymeric matrix, and wherein the secondary drug is dispersed in thethermoformable polymeric matrix.
 10. The method of claim 1, wherein theprimary drug-containing reservoir further comprises an adhesive.
 11. Themethod of claim 10, wherein the adhesive is a pressure-sensitiveadhesive.
 12. The method of claim 1, wherein the base layer is selectedfrom the group consisting of (i) a layer impermeable to one or more ofthe primary drug and the secondary drug and (ii) a drug release ratecontrolling layer.
 13. The method of claim 1, wherein the base layercomprises a material that is insoluble in water, alcohol, and organicsolvents.
 14. The method of claim 1, wherein the base layer isimpermeable to one or more of the primary drug and the secondary drug.15. The method of claim 1, wherein the base layer is a drug release ratecontrolling layer.
 16. The method of claim 15, wherein the drug releaserate controlling layer comprises a material selected from the groupconsisting of ethylene-vinyl acetate (EVA), polyvinyl chloride (PVC),ethylene-ethyl acrylate copolymer, ethylene butylacrylate copolymer,polyisobutylene (PIB), and polyethylene (PE).
 17. The method of claim 1,wherein the outer layer comprises an embossable, writable, andbreathable material.
 18. The method of claim 1, further comprisingmarking the device.
 19. A method of making a transdermal drug deliverydevice, the method comprising: obtaining a primary drug-containingreservoir comprising a primary drug selected from the group consistingof a therapeutic agent and an antagonist; obtaining a multilaminatebacking construction comprising (a) an outer layer, (b) a tie layercomprising a secondary drug-containing reservoir comprising a secondarydrug selected from the group consisting of an antagonist and atherapeutic agent, wherein the secondary drug is different from theprimary drug, and (c) a base layer; and coupling the primarydrug-containing reservoir to the multilaminate backing construction. 20.The method of claim 19, wherein the obtaining a multilaminate backingconstruction comprises laminating the outer layer and the base layer tothe tie layer.